Entresto for Tetralogy of Fallot and Ebstein's Anomaly

Overseen By Amanda Wozniak

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Mayo Clinic

Must not be taking: ACE inhibitors, ARBs, ARNI, others

Disqualifiers: Chronic kidney disease, Hyperkalemia, Hypotension, Pregnancy, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 52 weeks

45 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests how Entresto, a heart failure medication, affects adults with congenital heart disease, specifically Tetralogy of Fallot and Ebstein's Anomaly. Researchers aim to determine if Entresto can improve heart structure, function, and overall well-being compared to a placebo, which contains no active medicine. Participants should have a congenital heart disease diagnosis and should not have severe kidney problems or high potassium levels. This study suits adults living with these heart conditions who are not taking certain medications, such as ACE inhibitors or ARBs. As a Phase 3 trial, it represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

Yes, you will need to stop taking certain medications if you join this trial. Specifically, you cannot take medications like ACE inhibitors, ARBs, ARNIs, and several others listed in the exclusion criteria.

Is there any evidence suggesting that Entresto is likely to be safe for humans?

Research has shown that Entresto, a combination of sacubitril and valsartan, is generally easy for people to take. In the PARADIGM-HF study, Entresto was well-tolerated compared to other heart failure treatments, with fewer serious side effects reported. Studies have also examined its safety and effectiveness in people with congenital heart disease, including younger patients. These studies help ensure Entresto's safe use across different groups. The FDA has approved Entresto for treating heart failure, further supporting its known safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for congenital heart disease?

Unlike the standard treatments for Tetralogy of Fallot and Ebstein's Anomaly, which often include surgery and medications like beta-blockers or ACE inhibitors, Entresto offers a fresh approach by combining sacubitril and valsartan. This combination works uniquely by enhancing the heart's ability to relax and contract more effectively, thanks to its dual action of blocking harmful substances and promoting beneficial peptides. Researchers are excited about Entresto because it holds promise for improving heart function and quality of life in ways current therapies might not achieve.

What evidence suggests that Entresto might be an effective treatment for congenital heart disease?

Research has shown that Entresto, a combination of sacubitril and valsartan, yields promising results for heart conditions. In individuals with heart failure, Entresto improved heart function and reduced hospital visits. This trial will assess Entresto's potential benefits for congenital heart issues such as Tetralogy of Fallot and Ebstein's Anomaly. Participants will receive either Entresto or a placebo. Those with repaired Tetralogy of Fallot often experience heart problems, and Entresto might enhance their heart function and overall health. Previous studies indicate that Entresto is generally safe and well-tolerated. These findings suggest that Entresto could effectively improve heart health in people with these specific heart conditions. ^{1 2 3 6 7}

Who Is on the Research Team?

Alexander Egbe, MBBS, MPH

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

This trial is for patients with specific heart conditions known as Tetralogy of Fallot (TOF) and Ebstein's Anomaly (EA). Participants should meet certain health criteria to be included, but the provided information does not specify these. People with other conditions that could interfere with the study or pose a risk may be excluded.

Inclusion Criteria

TOF or EA

Exclusion Criteria

Pregnancy

Hyperkalemia defined as serum potassium >5.2 mmol/l

I am diagnosed with diabetes and am taking Aliskiren.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Entresto or placebo to assess changes in RV structure and function, biomarkers, and patient-reported outcomes

52 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Entresto

Trial Overview The study is testing Entresto, a medication for heart failure, against a placebo in patients with TOF and EA. It aims to observe any changes in the right ventricle's structure and function, biomarker levels, and patient-reported outcomes when taking Entresto compared to not receiving it.

How Is the Trial Designed?

Group I: Entresto Experimental Treatment 1 Intervention

Group II: Placebo Placebo Group 1 Intervention

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

In a systematic review of 21 studies involving 610 fetuses with Ebstein anomaly or tricuspid valve dysplasia, transplacental NSAID therapy resulted in significantly higher live birth rates (86%) and survival to hospital discharge (89%) compared to expectant management (67% and 43%, respectively).

While NSAID therapy showed potential benefits in improving outcomes, it was also associated with higher rates of complications such as moderate to severe tricuspid regurgitation and oligohydramnios, highlighting the need for caution and further research on its safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transplacental non-steroidal anti-inflammatory drugs versus expectant management in fetal Ebstein anomaly with circular shunt: Systematic review and meta-analysis. Mustafa, HJ., Aghajani, F., Bairmani, ZA., et al.[2023]

In a study of 341 adults with repaired tetralogy of Fallot, it was found that survival rates were significantly lower compared to the general population, especially in males over 55 years, indicating a heightened risk of premature death and arrhythmia.

Pulmonary valve replacement reduced right ventricle volumes and QRS duration but paradoxically increased the risk of adverse outcomes, suggesting that while it may alleviate some physical symptoms, it does not necessarily improve overall survival or exercise capacity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of adults with repaired tetralogy of Fallot from the national Scottish Cohort. Dobson, RJ., Ramparsad, N., Walker, NL., et al.[2021]

In a study of 72 unoperated adult patients with Ebstein anomaly, the most common initial presentation was arrhythmia, and the long-term survival was influenced by factors such as age at diagnosis, sex, and the severity of the heart's anatomy.

Despite initial symptoms often being mild, the study found that patients with Ebstein anomaly should not be viewed as low-risk, as significant morbidity and mortality were associated with factors like cardiothoracic ratio and echocardiographic severity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The adult patient with Ebstein anomaly. Outcome in 72 unoperated patients. Attie, F., Rosas, M., Rijlaarsdam, M., et al.[2019]

In a study of 85 adults with repaired tetralogy of Fallot (rTOF), pulmonary regurgitation and right ventricular outflow tract (RVOT) aneurysm or akinesia were found to be independently associated with right ventricular dilation and hypertrophy, which negatively impacted heart function.

The presence of RVOT aneurysm/akinesia was common in these patients and correlated with lower right ventricular ejection fraction (RVEF), highlighting the importance of maintaining pulmonary valve function to preserve overall heart health in individuals with rTOF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Right ventricular function in adults with repaired tetralogy of Fallot assessed with cardiovascular magnetic resonance imaging: detrimental role of right ventricular outflow aneurysms or akinesia and adverse right-to-left ventricular interaction. Davlouros, PA., Kilner, PJ., Hornung, TS., et al.[2019]

In a study of 144 patients who underwent surgical correction of tetralogy of Fallot before age 15, the cumulative survival rate was 72% after 40 years, indicating that long-term survival is achievable despite potential complications.

Most survivors reported a good quality of life comparable to the general population, although factors like previous shunt operations and early postoperative arrhythmias were linked to higher late mortality risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Unnatural history of tetralogy of Fallot: prospective follow-up of 40 years after surgical correction. Cuypers, JA., Menting, ME., Konings, EE., et al.[2022]

In a study of 191 patients who underwent tetralogy of Fallot repair, transannular patching was found to be a significant predictor of late adverse outcomes, including right ventricular dilatation, but did not lead to worse long-term functional outcomes compared to other patching methods.

Both transannular and right ventricular patching resulted in similar levels of long-term pulmonary insufficiency and right ventricular size, suggesting that the choice of patching technique may not significantly impact late outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tetralogy of Fallot: transannular and right ventricular patching equally affect late functional status. d'Udekem, Y., Ovaert, C., Grandjean, F., et al.[2022]

A machine learning model developed from clinical and cardiovascular data was able to predict major adverse cardiovascular events (MACE) in adults with repaired tetralogy of Fallot with a strong accuracy (area under the curve of 0.82) over a 5-year period, outperforming traditional prediction methods.

The model's effectiveness remained high even when limited to the top 10 predictive features, indicating that it can reliably use readily available clinical data for risk assessment, although removing exercise-related parameters decreased its predictive power.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Machine Learning for Prediction of Adverse Cardiovascular Events in Adults With Repaired Tetralogy of Fallot Using Clinical and Cardiovascular Magnetic Resonance Imaging Variables. Ishikita, A., McIntosh, C., Hanneman, K., et al.[2023]

Successful total repair of tetralogy of Fallot relies on understanding the complex anatomy and hemodynamics of the condition, which includes a large ventricular septal defect and significant right ventricular outflow obstruction.

In a study of 100 patients, the surgical approach led to a low mortality rate of only 3%, demonstrating the effectiveness and safety of the repair techniques when properly applied.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The surgical correction of Fallot's tetralogy. Barnard, CN., Barnard, MS.[2007]

A male infant with the rare combination of Ebstein's anomaly and tetralogy of Fallot presented with severe symptoms including cyanosis and heart failure, highlighting the critical nature of these congenital heart defects.

Successful biventricular repair was achieved in a single surgical procedure, correcting multiple issues including a ventricular septal defect and tricuspid regurgitation, leading to a positive recovery outcome for the infant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Surgical Correction for a Neonate With Ebstein's Anomaly Associated With Tetralogy of Fallot. Wei, LY., Shih, JC., Wu, ET., et al.[2017]

Advancements in cardiology have enabled many patients with congenital heart defects to live into adulthood, but they often face complications related to their defects or treatments, necessitating adult cardiologists to understand these conditions.

The guide provides essential information on common congenital heart defects seen in adults, including their anatomy, physiology, clinical presentations, complications, and treatment options, which is crucial for effective ongoing care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Congenital Heart Defects in Adults : A Field Guide for Cardiologists. Romfh, A., Pluchinotta, FR., Porayette, P., et al.[2021]

Citations

1. withpower.com withpower.com/trial/entresto-for-tetralogy-of-fallot-and-ebsteins-anomaly-9e69a

Entresto for Tetralogy of Fallot and Ebstein's Anomaly In a study of 341 adults with repaired tetralogy of Fallot, it was found that survival rates were significantly lower compared to the general population, ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S2666668521001920

Sacubitril/valsartan for heart failure in patients with ... Data regarding the safety and tolerability of ARNI comes predominantly from the PARADIGM-HF trial. This showed that ARNI was well tolerated compared to ...

3. link.springer.com link.springer.com/article/10.1007/s00246-025-03938-x

Single-Center Experience with Sacubitril/Valsartan in ... We observed an improvement in the ventricular systolic function in some of our patients, as well as a trend toward reduction in hospitalizations ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05963282

Comparative Effectiveness of Entresto (Sacubitril/Valsartan ... Comparative Effectiveness of Entresto (Sacubitril/​Valsartan) Versus ACEi/​ARB in de Novo Heart Failure Patients. ClinicalTrials.gov ID NCT05963282. Sponsor ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10061113/

The right ventricle in tetralogy of Fallot: adaptation to ... Right ventricular dysfunction is a major determinant of outcome in patients with complex congenital heart disease, as in tetralogy of Fallot.

6. mayo.edu mayo.edu/research/clinical-trials/cls-20575666

A Study of Entresto in Tetralogy of Fallot (TOF) ... The purpose of this study is to compare changes in RV structure and function, biomarkers, and patient reported outcomes between TOF patients ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S2666668521000203

The protocol and rationale for the efficacy aNd ToleRability ... The ENTRUST ACHD-HF registry will aim to assess the efficacy and tolerability of Sacubitril/Valsartan in the ACHD heart failure population.